Understanding antiretroviral (ARV) pharmacology in the genital tract (GT) is critically important, as these therapies have the potential to decrease sexual transmission of HIV by reducing HIV RNA and rendering the infected person less infectious, or by pre- or post-exposure prophylaxis. Low concentrations of ARVs in the GT may render pre-and post-exposure prophylaxis regimens ineffective, and may result in the emergence of drug resistant HIV mutations that could impact HIV transmission to others, and result in antiretroviral failure in an individual patient. This proposal examines the pharmacokinetic/pharmacodynamic relationships of ARVs and virologic response in the genital tract. Three Specific Aims are proposed. In Specific Aim 1, the complete pharmacokinetics of 14 ARVs in directly-aspirated female GT secretions will be determined. In Specific Aim 2, we propose to evaluate GT intracellular pharmacology by measuring nucleoside analogue mono, di, and triphosphate concentrations in male and female mononuclear cells derived from blood and GT secretions. In Specific Aim 3, HIV compartmentalization in the female genital tract will be assessed by developing pharmacokinetic/pharmacodynamic and statistical models to evaluate the relationship between virologic response rates in the female GT, and blood plasma HIV RNA, ARV exposure in blood plasma, and ARV exposure in the GT. The research projects described in this application form the core of a 5-year career development plan for Dr. Angela Kashuba, an assistant professor in the School of Pharmacy. Her mentor, Dr. Myron Cohen is an established HIV investigator, is Chief of the Division of Infectious Diseases (ID) in the School of Medicine, and Director of the UNC Center for Infectious Diseases (CFID). Her co-mentor Dr. Kim Brouwer has significant experience in the design, conduct, and analysis of clinical studies focusing on drug disposition and action. Her co-mentor Dr. Richard Tidwell has conducted extensive research in the design, testing and development of new agents for treatment of AIDS-associated opportunistic infections over the last 10 years. They propose a combined didactic and clinical research experience, utilizing the resources of the UNC CFAR and CFID, and the UNC General Clinical Research Center to foster Dr. Kashuba's research skills in evaluating ARV pharmacokinetic/pharmacodynamic relationships in the GT. They have assembled a carefully selected group of collaborators and advisors to assist in these research projects and Dr. Kashuba's career development. The long-term objectives of this project are to: 1) impact HIV transmission by advancing the science of ARV pharmacology and virology in the male and female GT in order to optimally chose effective combinations of antiretroviral therapies, and 2) to develop the applicant's skills in statistical, epidemiological, pharmacokinetic/dynamic modeling, and analytical methods in pharmacology pursuant to a career in clinical pharmacology research.